Risk of transmission of respiratory viruses during aerosol-generating medical procedures (AGMPs) revisited in the COVID-19 pandemic: a systematic review

Background In many jurisdictions healthcare workers (HCWs) are using respirators for aerosol-generating medical procedures (AGMPs) performed on adult and pediatric populations with all suspect/confirmed viral respiratory infections (VRIs). This systematic review assessed the risk of VRIs to HCWs in the presence of AGMPs, the role respirators versus medical/surgical masks have on reducing that risk, and if the risk to HCWs during AGMPs differed when caring for adult or pediatric patient populations. Main text We searched MEDLINE, EMBASE, Cochrane Central, Cochrane SR, CINAHL, COVID-19 specific resources, and MedRxiv for English and French articles from database inception to September 9, 2021. Independent reviewers screened abstracts using pre-defined criteria, reviewed full-text articles, selected relevant studies, abstracted data, and conducted quality assessments of all studies using the ROBINS-I risk of bias tool. Disagreements were resolved by consensus. Thirty-eight studies were included; 23 studies on COVID-19, 10 on SARS, and 5 on MERS/ influenza/other respiratory viruses. Two of the 16 studies which assessed associations found that HCWs were 1.7 to 2.5 times more likely to contract COVID-19 after exposure to AGMPs vs. not exposed to AGMPs. Eight studies reported statistically significant associations for nine specific AGMPs and transmission of SARS to HCWS. Intubation was consistently associated with an increased risk of SARS. HCWs were more likely (OR 2.05, 95% CI 1.2–3.4) to contract human coronaviruses when exposed to an AGMP in one study. There were no reported associations between AGMP exposure and transmission of influenza or in a single study on MERS. There was limited evidence supporting the use of a respirator over a medical/surgical mask during an AGMP to reduce the risk of viral transmission. One study described outcomes of HCWs exposed to a pediatric patient during intubation. Conclusion Exposure to an AGMP may increase the risk of transmission of COVID-19, SARS, and human coronaviruses to HCWs, however the evidence base is heterogenous and prone to confounding, particularly related to COVID-19. There continues to be a significant research gap in the epidemiology of the risk of VRIs among HCWs during AGMPs, particularly for pediatric patients. Further evidence is needed regarding what constitutes an AGMP. Supplementary Information The online version contains supplementary material available at 10.1186/s13756-022-01133-8.


Introduction
The emergence and ongoing worldwide spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causing the Coronavirus Disease 2019 (COVID-19) pandemic has led to much debate regarding the predominant routes of transmission of SARS-CoV-2 [1]. Over the course of the pandemic, the science of the modes of transmission of SARS-CoV-2 has evolved with increasing recognition that transmission occurs through multiple modes, including inoculation or inhalation of liquid particles of varying sizes from larger respiratory droplets to small aerosols which may come into contact with the mucous membranes of the respiratory tract or eyes as well as direct contact. An important emerging concept is that the respiratory particles represent a continuum along a spectrum of sizes from fine aerosols to large droplets [1][2][3][4][5][6]. The relative contribution of each transmission mode and how it may vary by setting and circumstance, however, is not well delineated and requires additional scientific study [1,[5][6][7]. In healthcare settings, transmission through the aerosolization of SARS-CoV-2, and other respiratory viral pathogens, may stem from specific medical procedures termed aerosol generating medical procedures (AGMPs) [5]. No universally agreed upon list or definition of AGMPs has been established for healthcare settings, and during the COVID-19 pandemic an increasing number of procedures have been considered by professional societies and organizations based on expert opinion [3,4,[8][9][10][11][12][13]. The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) consider open suctioning of airways, sputum induction, cardiopulmonary resuscitation, endotracheal intubation and extubation, non-invasive ventilation, bronchoscopy, and manual ventilation as AGMPs based on previous literature reviews [3,4,14]. These procedures were considered to generate higher concentrations of infectious respiratory aerosols based on epidemiological evidence, predominantly from case-control and retrospective cohort studies done on the transmission of SARS-CoV-1 or based on a theoretical risk of viral aerosolization and therefore increased risk of infection among healthcare workers (HCWs) [4,5]. As a result, international infection prevention and control guidelines have recommended personal protective equipment (PPE) include a high level of respiratory protection (i.e., N95 or equivalent particulate respirators) among HCWs when performing AGMPs on adult patients with suspected or confirmed acute viral respiratory infections (VRI) [3,9]. However, this recommendation varies across Canadian pediatric facilities.
An informal survey of ten Canadian pediatric hospital infection control programs in July 2021 showed that eight hospitals were using N95 respirators when performing AGMPs on patients with suspected or confirmed SARS-CoV-2 and MERS but not with other respiratory viruses, and two hospitals were also using N95 respirators with confirmed or suspected influenza (Lee BE, personal communication).
The COVID-19 pandemic resulted in the implementation of several public health and social measures (PHSMs) to mitigate spread, which have likely contributed to the significant reduction of seasonal respiratory viruses in Canada [15], US [16,17], and Europe [18,19]. With the increasing distribution of COVID-19 vaccines and as public health restrictions are lifted across jurisdictions, it is hypothesized that there will be a resurgence of some seasonal respiratory viruses, potentially during the troughs of the pandemic waves [17,19,20]. This "rebound effect" of VRIs [21][22][23] has already been reported in many countries, and is thought to be driven by the immunological deficit populations may have due to  PHSMs. Many jurisdictions are considering the use of particulate respirators for AGMPs performed on both adult and pediatric populations with all suspect or confirmed VRI. Therefore, the aim of this systematic review was to understand (1) the risk of respiratory viral transmission to HCWs in the presence of AGMPs, including relevant studies from the current COVID-19 pandemic; (2) what role N95 respirators versus medical/surgical masks have on reducing that risk; and (3) whether the overall risk to HCWs during AGMPs differed when caring for adult or pediatric patient populations.

Eligibility criteria
The population of interest were HCWs working in patient-facing roles at risk of contracting an acute VRI from the patient ( Table 1). The exposure of interest was performing, assisting, or being present during an AGMP. No restrictions were placed on PPE during AGMPs. The comparator of interest was not performing, assisting, or being present during an AGMP. Studies had to report the risk of transmission of a VRI to HCWs. VRI had to be confirmed by laboratory test (i.e., test for the presence of virus, viral antigens, or antibodies) or recognized case definitions (e.g., WHO criteria for SARS-CoV-1). All comparative studies were eligible for inclusion. Exclusion criteria were studies that did not report transmission of VRI to HCW (e.g. patient-to-patient transmission); no distinction between AGMP and non-AGMP groups; transmission of VRI that was not confirmed by lab test or established case definitions (e.g., reporting influenza-like symptoms); non-comparative study designs; editorials, case reports, and commentaries; non-English or French publications.

Information sources & search strategy
A systematic review of the literature was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [24] and reported in accordance with PRISMA 2020 reporting guidelines [25]. An experienced medical information specialist developed and tested the search strategies through an iterative process in consultation with the review team. The MEDLINE strategy was peer reviewed by another senior information specialist prior to execution using the PRESS Checklist [26].
Using the multifile option and deduplication tool available on the OVID platform, we searched Ovid MED-LINE ® , including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, EBM Reviews-Cochrane Central Register of Controlled Trials, and EBM Reviews-Cochrane Database of Systematic Reviews. We also searched CINAHL on Ebsco. The Ovid searches were performed on September 8, 2021, and the CINAHL search on September 9, 2021 from the inception of these databases to these dates.
We also searched COVID-specific resources (Cochrane COVID-19 Study Register, Covid-END, Living Overviews of Evidence (L-OVE), UNCOVER, ClinicalTrials. gov -Covid-19 resources, and the WHO Covid-19 Database) and the MedRxiv preprint server on September 9, 2021. This search was supplemented by hand-searching the reference lists of systematic literature reviews and recent health technology assessments, to ensure that all relevant studies were captured. Specific details regarding the strategies appear in Additional file 1.
The strategies utilized a combination of controlled vocabulary (e.g., "Aerosols", "Health Personnel", "Infectious Disease Transmission", "Patient-to-Professional") and keywords (e.g., "nebulize", "health care worker", "viral transmission"). Vocabulary and syntax were adjusted across the databases. The list of AGMPs included in the search was derived from the WHO, CDC lists based on previous systematic reviews and those included by expert opinion on the Alberta Health Services AGMP Guidance Tool, as of August 26, 2021 [13] (see Additional file 2). No language or date limits were applied in the search strategy, but animal-only records and conference abstracts were removed where possible. Results were downloaded and duplicates removed using EndNote version 9.3.3 (Clarivate Analytics) and uploaded to Microsoft Word.
This systematic review is registered in the International Prospective Register of Systematic Reviews (PROSPERO-CRD42021282323).

Selection process
Abstracts identified through database searching were screened in duplicate; all abstracts included at this stage by either reviewer proceeded to full-text review. Full-text publications were screened in duplicate. Any discrepancies between reviewers' inclusions were resolved through discussion between reviewers. A third-party adjudication process was used in the event of non-resolution between reviewers.

Data collection process
For all included studies, year of publication, country, study design and setting, patient characteristic (e.g., age and disease status), sample characteristics (e.g., HCW characteristics), type of AGMP, type and diagnosis of VRI, type of PPE, and all data on transmission of VRI were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers during data extraction were resolved through consensus. A third-party adjudication process was used in the event of non-resolution between reviewers.

Study risk of bias assessment
The quality of each included study was assessed using the Risk of Bias in Non-randomized Studies for Interventions tool (ROBINS-I) [27]. Each study was appraised using seven criteria broadly assessing bias due to confounding, selection of participants, classification of intervention/exposure, deviations from intended intervention/ exposure, missing data, measurement of outcomes, and selection of reported results. Quality assessment was completed in duplicate with discrepancies resolved through discussion. A third-party adjudication process was used in the event of non-resolution between reviewers. Studies were not excluded based on quality assessment.

Synthesis methods
Meta-analysis to pool unadjusted or adjusted odds ratios for studies that reported a statistical comparison between AGMPs and transmission of VRI was considered only if there were no heterogeneity between studies. Studies that reported only count data (e.g., number of events) where no statistical comparisons were made were summarized narratively and are not included in data exhibits. Crude or unadjusted odds ratios were not calculated manually for studies that reported only count data, as this would not take into consideration of any missing data (e.g., the true sample size was unknown). Data were reported and summarized narratively and in tabular form. Data were stratified by VRI type (e.g., COVID-19, SARS, MERS, Influenza, or other), and then by type of AGMP performed. Results pertaining to the secondary research question regarding the use of particulate respirators versus other PPE during AGMPs were narratively reported.

Study selection
The search strategy yielded 6624 unique citations, 6094 of which were excluded following abstract review (Fig. 1). One-hundred twenty-nine studies proceeded to full-text review where an additional 92 studies were excluded for the following reasons: comparator was not non-AGMP (n = 67); exposure was not an AGMP (n = 13); study design was not comparative (n = 7); outcome was not transmission of VRI (n = 2); duplicate study (n = 2); or the population was not HCWs (n = 1) (see Additional file 3  11:102 and are included in this evidence synthesis. Study characteristics of included studies are presented in Table 2.

Study risk of bias assessment
Quality assessment was conducted using the Cochrane risk of bias for non-randomized studies (ROBINS-I) [27]. Across the 38 included studies, overall risk of bias was serious for 29 studies (at least one domain was rated as serious), critical for seven studies (at least one domain was rated as critical) [33,35,41,48,[57][58][59] and moderate for two studies (no serious or critical ratings) [55,65] (Figs. 2 and 3).
On risk of bias due to confounding, most studies (n = 21) were rated as serious because confounding factors were not considered or controlled. Moderate ratings for 16 studies indicated that these studies attempted to control for confounding factors in their analysis. However, there was considerable heterogeneity in the characteristics or factors considered as confounders and how each study accounted for them in multivariate analysis in these studies. It should be noted that studies that presented adjusted odds ratios/ risk ratios are not reported in this review for consistency in results reporting. On risk of bias for participant selection, half of the included studies (n = 19) recruited all eligible HCWs at their site, or hospital ward of interest, therefore were rated low risk of bias. Serious (n = 13) and critical (n = 5) studies were rated as such when the participants were recruited based on the outcome of interest (e.g., case control studies that recruited COVID-19 positive, and COVID-19 negative HCWs). On bias in classification of intervention/ exposure, 19 studies were rated serious as they did not define what they considered to be AGMPs, 14 studies were moderate, three were low [35,44,45], and two were critical [58,59].
With respect to bias due to deviations from intended exposure, there was not enough information provided in the studies to rate on this domain. Because the studies do not comment on any known deviations from intended exposure, all studies were rated as "no information". For bias due to missing data, most studies were low, with the exception of two studies that were moderate due to missing data for more than five percent of the sample [38,57]. Bias in the measurement of the outcome was rated as low for 25 studies because diagnostic testing for VRI was conducted on all HCWs, regardless of exposure. Serious and moderate studies were rated as such if testing for VRI was dependent on the presence of symptoms (n = 8) [32,38,41,48,56,57,63,64], or known exposure (n = 5) [36,40,43,55,59], respectively. On bias regarding selection of reported results, 18 studies reported results on all outcomes that were outlined in their data analysis plan and were rated as moderate. Seventeen studies did not report their intended outcomes in their analysis plan, therefore were rated as serious. Three studies were rated as critical because they did not report a data analysis plan [33,41,57]. The only two studies which achieved a moderate level of risk of bias were consistent in their findings of an increased risk of transmission of SARS in association with intubation [55,65].           [54]. The remaining three studies reported event data only, with no statistical comparison reported [35,41,53]. Based on the level of heterogeneity between studies (e.g., variety of AGMPs included, degree of PPE, disease status of the patient), a meta-analysis on AGMPs which were not specified or were combined and the transmission of VRIs was not conducted. Across all pathogens, 22 studies reported transmission of VRIs during a specific, individual AGMP. Of these, 20 studies conducted a statistical test of significance between individual AGMPs and the transmission of COVID-19 (n = 10) [12,28,29,32,34,36,38,44,45,48], SARS (n = 8) [55,[58][59][60][62][63][64][65], MERS (n = 1) [54], or multiple VRIs (n = 1) [51]. The remaining two studies reported event data only, with no statistical comparison reported [57,61]. Based on the level of heterogeneity between studies, a meta-analysis on individual AGMPs and the transmission of VRIs was not conducted.
A more detailed synthesis stratified by VRI is presented below.

COVID-19 AGMPs not specifically identified
Nineteen studies (50%) explored transmission of COVID-19 to HCWs after exposure to AGMPs which were not specifically identified (n = 5) or were combined (n = 14). Three studies reported count data only and did not conduct a statistical analysis for the association between AGMPs which were not specified or combined and transmission of COVID-19 [33,35,41]. For the 16 studies [30-32, 36, 37, 39, 40, 42-50] that reported results from a test of statistical significance, the results can be found in Table 3, grouped by study design. There were four statistically significant associations for transmission of COVID-19 to HCWs exposed to AGMPs in three separate studies and one study close to reaching statistical significance [45]. Of the two studies that reported statistically significant odds ratios, HCWs were 1.7 to 2.5 times more likely to contract COVID-19 after exposure to AGMP versus HCWs who were not exposed to AGMP. Only five studies accounted for confounding in adjusted measures of effect [32,39,44,47,49]. Pérez-Garcia et al. [47] found that participation in an AGMP no longer increased risk to HCWs when accounting for use of PPE, close vs. casual contact, and contact with COVID-19 patients. Paris et al. [44] found an increased risk of COVID-19 during an AGMP when adjusted for age, sex, occupation, and contact with COVID-19 patient or relative at home. Lentz et al. and Vitrat et al. [32,39] saw no change in results when adjusting for confounders. Studies which demonstrated no associations were generally smaller or those which had no actual reported discrete sample sizes.

Not specifically identified AGMPs
No studies reported statistical associations for the transmission of SARS to HCWs after exposure to AGMPs not specifically identified.

MERS
One study looked at MERS infection among a cohort of HCWs who reported direct contact (i.e. within 2 m) with a MERS patient in the hospital. No statistically significant difference in seropositivity in HCWs was observed for manipulation of oxygen face mask or tubing, airway suction, non-invasive ventilation, manual ventilation, nebulizer treatments, intubation, CPR, high-frequency oscillatory ventilation, bronchoscopy, or extubation.
Overall, there was no statistically significant difference in seropositivity in HCWs present in the room when any of these procedures were performed [54].

Other coronaviruses
In the study looking at various coronavirus strains HKU1, OC43, NL63, 229E, HCWs were 1.77 times more likely to contract the virus if they participated in airway suctioning (OR = 1.77, 95% CI: 1.19 to 2.57), 2.01 times if they participated in nasopharyngeal aspiration (OR = 2.01, 95% CI: 1.27 to 3.04), and 1.81 times if they participated in nebulizer treatment (OR = 1.81, 95% CI: 1.34 to 2.42); no statistically significant differences were observed for intubation; a pooled OR of all these activities revealed that HCWs who participated in them were 2.05 times more likely to contract any one of the human CoVs (OR = 2.05, 95% CI: 1.21 to 3.4) [51]. This risk was reduced but remained significant (aOR 1.80, 95% CI 1.04-3.1) when adjusting for age, household members under the age of 5 years, whether participants saw adult, pediatric or both patient populations, the proportion workdays with exposure to patients or co-workers with respiratory illness, and occupational risk level [51].

Other pathogens
Across the included studies, three reported on influenza [52,53,56], including one that reported on several *Bolded estimates represent statistically significant results (p < 0.05). Details pertaining to patients and settings and studies that only reported count data but no statistical comparisons can be found in Table 2 AGMP aerosol-generating medical procedure; aOR adjusted Odds Ratio; aHR adjusted Hazard Ratios; NR not reported; CI confidence interval; RR risk ratio; IRR incidence rate ratio; PR prevalence ratio a Unadjusted Odds Ratio unless otherwise specified b Adjusted Odds Ratios of SARS-CoV-2 seroconversion reported because unadjusted odds ratios could not be found c Adjusted Hazard Ratios of SARS-CoV-2 PCR/rapid antigen tests reported because unadjusted odds ratios could not be found d AGMP status of comparator unclear e AGMP with systematic use of FFP2 compared to non-AGMP exposure f AGMP without systematic use of FFP2 compared to non-AGMP exposure   [56]. These three studies did not report statistical comparisons for specific AGMPs.

Influenza
Two of the three influenza studies reported statistical comparisons between the AGMP and non-AGMP groups; in both studies, there were no statistically significant differences in VRI rates between HCWs in AGMP and non-AGMP groups [52,56]. One study adjusted for other variables (e.g. number of hours worked, number of patients the HCW was in contact with, number of contacts with patients with ILI) and found no significant association between influenza and AGMPs [56].

Multiple pathogens
In one study examining various pathogens, HCWs performing AGMPs were 2.5 times more likely to contract the respiratory infection based on the presence of respiratory symptoms (OR = 2.5, 95% CI: 1.3 to 6.5; p < 0.01); this effect, however, was not significant when looking only at laboratory-confirmed viral infection by influenza combined with human coronavirus 229E/NL63, rhinoviruses, and respiratory syncytial viruses (OR = 2.8, 95% CI: 0.9 to 8.7, p = 0.07) [56]. However in a more robust Poisson regression analysis, adjusted for HCW age, education, occupation, history of influenza vaccine, and hand hygiene for the outcome of laboratory-confirmed viral infection, the RR of 3·3 (95% CI 1·01-11·02, p = 0·05) was significantly associated with the performance of an AGMP (defined as nebulizer medications, suctioning, intubation, aerosol-generating procedures and chest physiotherapy). Respiratory airway suctioning was the most common AGMP with 66% of respondents reported performing this procedure. Respondents represented a convenience sample of HCWs from a control group of a larger RCT, who did not wear a mask and who did not have any interventions on the use of masks or respirators and being observed in their usual working conditions [67].

COVID-19
An international case-control study reported that wearing a respirator (N95/FFP2/FFP3/PAPRs/reusable elastomeric respirators) during AGMPs and non-AGMPs had a 60% reduced risk (aOR 0.4, 95%CI: 0.2-0.8, p = 0.005) of contracting COVID-19 when exposed to COVID-19 patients, versus HCWs who did not report wearing a respirator during AGMPs and Bolded estimates represent statistically significant results (p < 0.05). Details pertaining to patients and settings and studies that only reported count data but no statistical comparisons can be found in Table 2 AGMP aerosol-generating medical procedure; CI confidence interval; RR risk ratio a Odds Ratio unless otherwise specified b Adjusted odds ratio reported because unadjusted odds ratios could not be found  [32].
In a retrospective cohort study where all HCW used either a respirator or surgical mask during an AGMP, they found the use of a surgical mask instead of respirator during AGMP was not associated with transmission of COVID-19 even in the context of a prolonged (≥ 5 min) close contact (< 2 m or 6 ft) to a patient with confirmed COVID-19 (RR 0.99; 95% CI 0.96-1; p = 1) [40].
Three other studies reported the use of respirators (N95/KN95/FFP2) during AGMPs as either increasing or reducing the risk of COVID-19, however it was not clear whether this was compared to medical/surgical masks [41,46,50].
An additional two studies reported the risk of COVID-19 among HCWs exposed to AGMPs compared to non-AGMP exposures, where the AGMP group was stratified by appropriate/systematic or sub-optimal/nonsystematic use of masks [39,44]. For AGMPs with selfdeclared appropriate, or sub-optimal mask use there was an increased association with a positive test for SARS-CoV-2 IgG (OR 1.37, 95% CI 1.04 to 1.81; and OR 1.74, 95% CI 1.05 to 2.88, respectively) [44]. The systematic use of FFP2 during AGMPs compared to non-AGMP exposures, decreased the serological prevalence of COVID-19 when compared to the serological prevalence of COVID-19 after exposure to AGMPs without the systematic use of FFP2 (OR 1.70; 95% CI 1.15 to 2.49, and OR 2.03; 95% CI 1.36 to 3.02, respectively); however the 95% CI cross each other and therefore there is no statistical significance between AGMP exposures [39].

SARS and MERS
In a retrospective cohort of MERS, HCWs who reported always covering their nose and mouth with either a medical mask or N95 respirator while present in the room during an AGMP had a 68% lower risk for infection than HCWs reporting not always or never doing so (RR 0.32 95%CI 0.12-0.86, p = 0.03); however when medical masks or N95 respirators always worn during AGMPs were evaluated independently and compared to sometimes/never worn during AGMPs, both showed a protective effect but were not statistically significant [54].
A study on the risk of SARS to HCWs providing care to intubated SARS patients showed that HCWs who contracted SARS were more likely to have used less effective methods of respiratory protection while in a patient's room (Cochran-Armitage test for trend for no respiratory protection, to surgical mask, to N95 or equivalent to protection higher than N95, p = 0.04) [55].

Discussion
Thirty-eight studies were identified in this systematic review on the risk of viral transmission in the presence of AGMPs, with 60% of studies focused on COVID-19 and therefore published within the past two years. Based on the studies assessed in this review, exposure to an AGMP may increase the risk of respiratory viral transmission to HCWs, however the evidence base is inconsistent, particularly related to the transmission of COVID-19. Most of the studies were on COVID-19 and SARS with only three studies on influenza, one study on other human coronaviruses, one on MERS and one study with multiple respiratory viruses where the HCWs were a no-mask control group for a clinical trial [67]. For COVID-19, of the 16 studies that reported unadjusted results, two studies revealed an increased risk of transmission of COVID-19 to HCWs exposed to either not specified or combined AGMPs, reaching statistical significance. When adjusting for different confounders, the results also varied between demonstrating an increased risk of transmission and not. These were cross-sectional studies and one was a preprint manuscript not yet peer-reviewed [46] but they were among the largest of the studies. One prospective cohort study found a trend towards a significant association for all AGMPs combined and found significant associations of transmission with specific AGMPs [45]. This study used both RT-PCR and serology for case ascertainment. Studies that did not show a statistically significant relationship between AGMPs and COVID-19 varied in study design, AGMPs and HCW role during the AGMP, and sample sizes were small or not reported.
Eight of the ten SARS studies reported statistical associations for nine specific AGMPs and the transmission of SARS. Six of these studies demonstrated increased risk of transmission of SARS with a specific AGMP, reaching statistical significance. Of the two studies that did not report a statistical association between a specific AGMP and the transmission of SARS, one reported proportions of HCWs who did not develop SARS with exposure to nebulized medications or NIPPV [61] and the other studied medical students present in a room during nebulization therapy but who had been previously exposed from a different source [57], which compromises meaningful interpretation. All but one study reported associations for SARS transmission during intubation that were statistically significant including the two moderately rated studies on risk of bias. The one study on human coronavirus infections reported statistically significant associations with various AGMPs and for the one MERS study there was no statistically significant difference in seropositivity in HCWs across any of the specific AGMPs.
Another study on mixed VRIs also revealed statistically significant associations for transmission to HCWs during the performance of AGMPs [56].
A systematic review previously published by Tran et al. [14] also evaluated the risk of transmission of acute respiratory infections to HCWs exposed to AGMPs. Their review identified ten studies, all investigating the risk of transmission of SARS to HCWs exposed and not exposed to AGMPs. They concluded that some procedures potentially capable of generating aerosols were epidemiologically associated with an increased risk of SARS transmission to HCWs, with the most consistent association observed with tracheal intubation [14]. However, the precision of the reported statistical associations was wide among the studies included in the Tran et al. review and they also acknowledged that the study quality was low. Nonetheless, the associations were quite consistent across the studies which added epidemiologic strength to the association with respect to SARS. Only one of the five studies in this review was found to have a significant statistical association between tracheal intubation and the risk of COVID-19, however details about the patient exposure were not provided [28].
There was limited evidence supporting the use of a particulate respirator over a medical/surgical mask during an AGMP to reduce the risk of viral transmission. Only one study reported a statistically significant, 60% reduction in the risk of contracting COVID-19 among HCWs wearing a respirator during an AGMP [32]. One study indicated that risk of infection during an AGMP (across various viral pathogens) was higher amongst HCWs who did not wear a mask or respirator as compared to those who did [56]. RCTs and cluster-RCTs comparing N95 respirators and medical/surgical masks have primarily been conducted during routine care of patients, not AGMPs, with VRIs in healthcare settings (n = 5 studies) and households (n = 1 study). These studies revealed that N95 respirators compared to medical/surgical masks made no significant differences in transmission of laboratory-confirmed influenza for routine care with moderate certainty evidence [68].
No conclusions could be made on the relative risk of VRI to HCWs during AGMPs between pediatric and adult patient populations. The lack of pediatric specific data makes it challenging to draw firm conclusions or make recommendations for those HCWs caring for pediatric patients. Only one small study described the outcomes of 11 HCWs exposed to a pediatric (17-yearold) patient with asymptomatic COVID-19 during endotracheal intubation. Nine of the HCWs did not wear N95 respirators during the procedure, and no cases of COVID-19 occurred [41]. In the post-hoc analysis of the ResPECT study, HCWs that saw pediatric patients had a 57% increased odds of coronavirus infection compared to those that saw only adult patients [51]. However, there was no analysis assessing whether this risk was related to AGMPs or not. Based on the recent environmental scan of pediatric facilities in Canada, no consensus on the use of respirators for endemic or emerging/re-emerging respiratory pathogens has been clearly established.
Ninety-five per cent of the studies had an overall serious or critical risk of bias. First, there were issues related to study design. Many studies were cross-sectional or retrospective observational studies, limiting our understanding of directionality between AGMP exposure and the VRI outcome.
The comparison of HCWs performing AGMPs vs not performing AGMPs is difficult, indirect, and prone to significant confounding. Most studies did not consider or control for confounding factors when assessing the risk of VRI in the presence of AGMPs such as the use of PPE, disease status of the patient, days from symptom onset, vaccination status of the patient and/or HCWs, exposure time to the patient with VRI, training and experience of the AGMP operator, or other potentially clinically relevant details such as whether or not anesthesia or paralysis is involved with procedures such as intubation. Some clinical scenarios are managed in ways that may ultimately reduce the risk of transmission that effectively negate aerosol generation or regardless of which respiratory protection is used. Consideration of communitylevel prevalence, increased transmissibility of variants of concern in the context of COVID-19, and procedure room ventilation, were not discussed.
Second, no genomic testing of viral pathogens among HCWs and patients were reported to verify transmission of the same strain.
Third, many studies used questionnaires to retrospectively collect exposure information from HCWs at varying follow-up periods, introducing recall bias in the study and further limiting our understanding of the directionality between AGMP exposure and the VRI outcome.
Finally, over half of the studies did not list specific AGMPs but instead combined multiple procedures into the category of AGMP or did not define their AGMP group. Lack of describing the AGMP and identifying potential confounders precludes distinguishing whether the increased risk of VRI during AGMPs is due to the procedure itself or the circumstances in which the procedures are being performed [4,14,69,70]. For example, the increased risk observed among certain procedures may be explained by symptoms experienced by the patient, viral load, proximity of the HCW to the patient during the procedure, and duration of the exposure [4,70]. Similarly, PPE use was poorly reported, and the effect of PPE was seldom controlled for in the statistical comparisons within the studies. Where it was reported, it was self-reported leaving room for recall bias or it was not always measured in the same way (e.g., percentage of time PPE was used properly vs. dichotomous measure of always or sometimes used). Therefore, it is unknown if the difference in risk among AGMPs was due to exposure to the AGMP itself or exposure to an AGMP with inappropriate PPE or lapses in adherence to PPE.
Another issue highlighted by this systematic review was the lack of a definitive and comprehensive list of AGMPs for healthcare settings. Tran et al. [14] acknowledged the presence of a significant research gap in the epidemiology of the risk of transmission of VRI from patients undergoing AGMPs to HCWs and the difficulty in defining AGMPs. Specifically, the scientific evidence for the creation of aerosols associated with the procedures and the burden of infectious microbes within the created aerosols, and the mode of transmission were not well studied. In their conclusions, they suggested that funding agencies should focus attention on this area. Many organizations or professional societies have itemized AGMPs [3,4,[8][9][10][11][12][13] but not all of these procedures were identified based on formal measures of potential infectious aerosols produced by the procedure or robust epidemiological studies demonstrating increased risk of infection to HCWs or others exposed to patients undergoing these procedures [69]. This continue to be the case, as most procedures listed as AGMPs have limited data characterizing the creation and dispersion of aerosols and the quantification of infectious agents from the aerosols [71,72]. Therefore, further rigourous multidisciplinary research is needed to understand the relative increase in infectious aerosols by these procedures relative to symptoms of illness that may generate aerosols (e.g. coughing and sneezing).
We also agree that more rigorous studies should be conducted to understand the factors that lead to increased transmission risk, which not only consider the procedures that are being performed but also the specific pathogens, the circumstances surrounding the patient with respect to the procedure and their state of illness and immunity; and HCW related factors such as immunity, PPE, and general health.
In this review, pooled effect sizes were not calculated due to the heterogeneity in the studies including variations in the jurisdiction, viral pathogen, type of AGMP, and consideration of confounding factors. The precision of the reported statistical associations was wide across several studies making it difficult to infer the true effect size. We were unable to identify sufficient evidence to make any conclusions regarding the type of mask (medical/surgical mask or respirator) that should be used during AGMPs. Specific AGMPs could not be delineated from the grouped analyses in most studies on SARS-CoV-2 and therefore risk could not be assigned to individual procedures. Although some studies examined the risk of VRI among HCWs caring for pediatric and adult patients undergoing AGMPs, the ability to pull the pediatric information into a discrete number was not possible.
Despite these limitations our systematic review has several strengths including the comprehensive search, inclusion of medical procedures traditionally considered AGMPs, the inclusion of procedures identified by consensus by our AGMP working group which expanded upon the traditional list; a search for studies that assessed the risk to HCWs during AGMPs in pediatric populations specifically, and the evaluation of studies exploring the role of medical/surgical masks versus respirators during AGMPs. We did not identify any recent studies after our search date that would change our overall findings. In addition, this review looked at all members of the coronavirus family and was unique in this approach and found there may be an increased risk of transmission with AGMPs and of any of the coronaviruses except for MERS.

Conclusion
The findings from this systematic review, mainly of unadjusted comparisons from observational studies, suggest that there may be an elevated risk of transmission with AGMPs for SARS, COVID-19, and human coronaviruses. What proportion of that effect is due to confounding, and what proportion is due to a true effect is unknown and needs careful evaluation in future studies of higher quality that take confounding into consideration. Evidence of the difference in protection between medical masks and